Dengue virus (DEN), a priority "A" pathogen on the NIH/CDC list of bioterrorism related and emerging pathogens, infects humans causing a spectrum of clinical manifestations including dengue fever, dengue hemorrhagic fever and dengue shock syndrome. Severe disease is associated with a second infection with a different serotype or infection of infants harboring maternal antibodies. One of the challenges to development of an effective DEN vaccine is to induce active immunity in the face of maternal antibodies, a problem also facing vaccines for measles and other diseases. We hypothesize that a vaccine for DEN based on non-propagating Venezuelan equine encephalitis virus vectors (VRP) will be able to induce an endogenous immune response in young mice, even in the presence of passively transferred neutralizing anti-DEN antibodies. We base our hypothesis on three properties of the VEE vectors, (i) The DEN antigens will not be exposed on the VRP surface, (ii) VRP will target the antigen-encoding gene to the lymph node, facilitating and enhancing antigen presentation, (iii) Non-propagating VRP vectors immunize by expressing high levels of the heterologous gene only in a single round of infection. In this exploratory grant we propose to 1) Characterize the baseline humoral and cell-mediated immune responses induced by a prototype VRP vaccine expressing DEN2 prM and E membrane proteins in weanling mice; 2) Determine the ability of the prototype vaccine to induce an endogenous immune response in weanling mice in the presence of neutralizing anti-dengue antibodies passively transferred by inoculation or by suckling on immune dams; and 3) Modify the intracellular targeting of the VRP-expressed DEN2 prM and E proteins to improve expression levels and immunogenicity in mice. These experiments will demonstrate the feasibility of a VRP approach to a tetravalent DEN vaccine while suggesting solutions to similar difficulties with maternal antibodies encountered with other infant vaccines including measles.